Drug delivery, and drugs incorporating drug delivery systems, are gaining increased interest. New drug delivery systems, including nasal sprays, extended-release oral formulations, topical creams, transdermal patches and inhalational compounds have the capacity to expand the convenience and usefulness of therapeutic agents, e.g. peptides. Conventionally, most of these compounds have been either administered by injection only or abandoned because of poor bioavailability and/or solubility. Novel drug delivery technologies offer new capabilities to revive the market potential by unleashing the therapeutic capabilities of these compounds, providing new solutions to old problems.
The transdermal administration of drugs is becoming increasingly accepted as a preferred mode of delivery. Transdermal delivery of drugs provides many advantages over conventional oral administration, including convenience, non-interrupted therapy, improved patient compliance, reversibility of treatment (by removal of the system from the skin), elimination of the “hepatic first pass” effect, a higher degree of control over blood concentration of any particular drug, and a consequent reduction of side effects.
Transdermal delivery of drugs requires transport of the drug molecules through the stratum corneum, i.e., the outermost layer of the skin. The stratum corneum (“SC”) provides a formidable chemical barrier to any chemical entering the body, and only small molecules, with molecular weights less than 500 Daltons (“Da”), can passively diffuse through the SC at rates that enable therapeutic effects. (A Dalton is a unit of molecular weight as compared to the hydrogen atom.)
U.S. Pat. No. 5,733,572, to Unger, et al., describes compositions comprising gas and/or gaseous precursor filled microspheres, which include an active ingredient for application to tissue of a patient. The gas in the microspheres may serve to prevent oxidation and other forms of degradation of active ingredients, such as labile drugs, bioactive compounds and cosmetics, and the microspheres may be formed from, e.g., a biocompatible lipid or polymer. The lipid may be in the form of a monolayer or bilayer, and the mono- or bilayer lipids may be used to form a series of concentric mono- or bilayers. Thus, the lipid may be used to form a unilamellar liposome (comprised of one monolayer or bilayer lipid), an oligolamellar liposome (comprised of two or three monolayer or bilayer lipids) or a multilamellar liposome (comprised of more than three monolayer or bilayer lipids). Preferably, the biocompatible lipid is a phospholipid. The resultant gas or gaseous precursor filled microsphere composition, which often takes the form of a foam, provides a very creamy texture and skin penetration enhancing qualities for the topical or subcutaneous delivery of active ingredients. The active ingredients include drugs, especially peptides and other bioactive compounds, as well as cosmetics.
U.S. Pat. No. 4,558,690, to Joyce, “Method of Administration of Chemotherapy to Tumors,” assigned to University of Scranton, describes an anticancer capsule comprising an anti-neoplastic agent encapsulated in a meltable polymer. Polyoctadecyl acrylate, a side-chain crystallizable polymer, is used as the meltable polymer. Once the composition has been delivered to the tumor, nonionizing radiation is used to locally heat the tumor and melt the capsule wall so that it disintegrates and permits the agent to be released by dissolution. Drug release does not occur via diffusion through the polymer.
U.S. Pat. No. 3,242,051, to Hiestand, et al., mentions polyvinyl stearate, another side-chain crystallizable polymer, as a precoating material in a two-step microencapsulation process. A described embodiment is a dose of 30 mg of methotrexate (A-methopterin) in the form of spherical microcapsules having an average of 200-800 microns diameter and a polymer of olystearyl acrylate encapsulating coating of an average thickness of 1-50 microns. This dose is injected into the tumor and released by a 30-60 minute irradiation of the tumor by 175-200 watts f RF non-ionizing radiation at a frequency of 13.56 megaHertz from a set of capacitive plates positioned on opposite sides of the impregnated tumors. The tumor temperature is elevated to a threshold temperature of 430° C., which is the melting point and release point of the encapsulated acrylic resin. The temperature of the rest of the organism outside the tumor remains at 390-400° C., which is below the release temperature of the resin.
U.S. Pat. No. 5,190,766, to Ishihara, et al., “Method of Controlling Drug Release by Resonant Sound Wave,” assigned to Ken Ishihara (Hyogo, J P), describes a drug carrier carrying a drug, which is introduced to a diseased region of the living body while it is observed in the B mode echograms. The drug carrier is irradiated with an ultrasonic wave for strongly vibrating the drug carrier, thereby releasing the drug from the drug carrier for curing the diseased portion.
U.S. Pat. No. 5,614,212 to D'Angelo, et al., “Method of Transdermally Administering High Molecular Weight Drugs with a Polymer Skin Enhancer,” assigned to International Medical Associates, Inc., describes a method of administering transdermally a high molecular weight drug by applying a polymer skin enhancer and a drug active to the skin of the patient. The drug active has a molecular weight of above 500 Daltons. The drug may be encapsulated or the drug solution may be partly encapsulated and partly free. The skin enhancer is preferably polyvinylpyrrolidone (PVP) and it is mixed at between 7 and 35% of the drug. A gelling agent may be optionally added at up to 20% by volume. The chemical system is preferably administered via a multidose transdermal drug patch assembly, which includes a drug-impervious support impressed to form a series of compartments. Each compartment is a reservoir for a unit dose of a drug active to be transdermally administered. The support is adhesively secured to the skin of a patient. Individual devices are provided for resealably enclosing the drug active in each of the reservoirs. The individual enclosing devices are removable to release the unit dose into contact with the skin of the patient and are actuable to control the transdermal absorption of the drug actives. The drug may also be administered in a cream.
Several methods have been proposed to facilitate transdermal delivery of molecules larger than 500 Da and increase the rate of drug delivery through the SC, including iontophoresis, electroporation, electroincorporation, sonophoresis and chemical enhancers.
The iontophoresis method utilizes low electric fields to drive drug molecules into the skin, as described in U.S. Pat. No. 5,224,927. However, iontophoresis is to greater extent limited to ionizable drugs and molecules and is ineffective for molecules with molecular weights greater than about 7,000 Da (i.e. 7 kDa), as described by N. G. Turner, et al., in Pharm. Research 14,1322-1331 (1997).
The electroporation and electroincorporation methods utilize high voltage electric pulses of 150 V that are directly applied to the skin, as described in U.S. Pat. No. 5,019,034. The electric pulses help open pores in the skin, thus allowing molecules above 7 kDa to pass through the skin. However, the use of high electric voltages poses safety problems and requires complicated equipment. Furthermore, the drugs need to be driven through the pores by some secondary means, e.g. as described in U.S. Pat. No. 5,688,233, which further complicates the application.
The sonophoresis method utilizes ultrasound and has been shown to be capable of delivering molecules up to 48 kDa, as described in U.S. Pat. No. 5,814,599 and U.S. Pat. No. 5,947,921.
However, the rate of delivery is extremely low, thus rendering it impractical. In the recently issued U.S. Pat. No. 6,487,447 of which the present applicant is a co-inventor, it was shown that transdermal passage of large polypeptide molecules can be accomplished using sonomacroporation.
Chemical enhancers such as unsaturated fatty acids, saturated fatty acids, their esters and terpenes can increase the flux through the SC for drugs having large molecular weights, such as estradiol, testosterone, and also polar drugs such as hydrochloride salts of basic drugs (e.g., propranolol.HCI), as described by J. R. Kunta, V. R. Goskonda, H. O. Brotherton, M. A. Khan, and I. K. Reddy., “Effect of Menthol and Related Terpenes on the Percutanious Absorption of Propranolol Across Excised Hairless Mouse Akin” J. Pharm. Sci. v.86, no. 12, 1369-1373 (1997), and in U.S. Pat. No. 5,947,921. However, chemical enhancers have serious formulation problems; they can cause skin irritations and unwanted plasticization of the transdermal patch adhesive used for their application; and their effectiveness depends upon the drug type and its application method.
Although transdermal systems have many advantages, most drugs are not amenable to this mode of administration due to their incompatibility with the carrier matrix or their instability in the carrier matrix environment.
Partitioning of a drug into the skin is dependent on the difference in the chemical potentials of the drug in the carrier matrix and the skin. Pressure-sensitive adhesives are relatively lipophilic, having solubility parameters very close to that of the skin. See, e.g. CRC Handbook of Solubility Parameters and Other Cohesion Parameters, 2nd Ed., by A. F. M. Barton, especially sec. 2.2. The driving force of the drug from the carrier matrix to skin is directly proportional to the difference between the solubility parameters of the drug and the carrier matrix, and is inversely proportional to the difference between the solubility parameters of the drug and the skin.
Chemical enhancers such as unsaturated fatty acids, saturated fatty acids, their esters and terpenes, showed flux increases of drugs with larger molecular weights such as estradiol and testosterone, and also polar drugs such as hydrochloride salts of basic drugs (e.g., propranolol-HCl), as described in J. R. Kunta, et al, in J. Pharm. Sci. 86, 1369-1373 (1997), cited above. Practical use of chemical enhancers, however, is not yet very advanced due to serious formulating obstacles. Their enhancing properties are both vehicle- and drug-dependent; they also cause unwanted plasticization of the transdermal patch adhesive. Also liquid drugs, such as scopolamine or active agents such as nicotine, cause unwanted plasticization of the adhesive, affecting manufacturing efficiency due to problems with slitting and die cutting of the oozing laminates.
A number of drugs and active agents are not stable once dispersed in the matrix of an adhesive. For example, Vitamin C is unstable in aqueous solutions and is easy oxidizable in the matrix. Insulin, too, is very unstable in an adhesive matrix.
Presently marketed transdermal patches begin the delivery of a drug or other active substance to be delivered transdermally immediately upon being placed on the skin. In such a situation, the transdermal drug delivery kinetic profile is dependent on the fixed size of the patch and the fixed drug concentration in the matrix. Such patches cannot deliver a drug or other active substance to be delivered transdermally “as needed.”